Journal
SCIENCE IMMUNOLOGY
Volume 4, Issue 39, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aau8943
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Funding
- Deutsche Forschungsgemeinschaft (DFG
- German Research Foundation) [360372040 -SFB 1335, 395357507 -SFB 1371, PO 1575/3-1]
- Else-Kroner-Fresenius-Stiftung [2012_A61, 2015_A06]
- Melanoma Research Alliance
- Alexander von Humboldt Foundation
- German Cancer Aid [111620]
- European Hematology Association
- Mechtild Harf Research Grant from the DKMS Foundation for Giving Life
- Dres. Carl Maximilian and Carl Manfred Bayer Foundation
- European Research Council [CoG2015_682473_BCM-UPS]
- EMBO Young Investigator Program
- TUM University Foundation
- Else-Kroner-Fresenius-Stiftung (EKFK)
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Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti-CTLA-4 and its combination with anti-PD-1 rely on tumor cell-intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell-intrinsic RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103(+) dendritic cells, subsequent expansion of tumor antigen-specific CD8(+) T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5'-triphosphorylated RNA in both tumor and nonmalignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of DDX58 (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity, and prolonged overall survival. Moreover, in patients with melanoma treated with anti-CTLA-4 checkpoint blockade, high DDX58 RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer.
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